CN111467568B - Cross-linked sodium hyaluronate composite solution preparation and preparation method and application thereof - Google Patents
Cross-linked sodium hyaluronate composite solution preparation and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a cross-linked sodium hyaluronate composite solution preparation and a preparation method and application thereof. The cross-linked sodium hyaluronate composite solution preparation comprises: 1-20 mg/mL of cross-linked sodium hyaluronate; 0.1-20 mg/mL of water-soluble non-crosslinked polymeric polysaccharide or salt form thereof; 0-20 mg/mL of polypeptide; 0-10 mg/mL of amino acid; 0-50 mu g/mL of vitamin. Compared with the common crosslinked sodium hyaluronate filling material, the crosslinked sodium hyaluronate composite solution preparation has lower viscosity and better fluidity; compared with non-crosslinked sodium hyaluronate, the degradation time is longer. The product of the invention can be used for correcting human wrinkles such as facial wrinkles, eye wrinkles, forehead wrinkles, neck wrinkles, hand wrinkles, pregnancy lines and the like by using an intradermal injection mode.
Description
Technical Field
The invention belongs to the field of implanted medical instruments and skin nutrition, and particularly relates to a cross-linked sodium hyaluronate composite solution preparation as well as a preparation method and application thereof. The compound solution preparation can fill skin superficial layer of skin wrinkles and has nourishing effect on skin extracellular matrix.
Background
Due to the influence of factors such as heredity, environment and the like, the skin can be gradually aged, various skin aging symptoms appear, wrinkles are one of the symptoms, and facial wrinkles, periocular wrinkles, forehead lines, neck lines, hand wrinkles, pregnancy lines and the like are common.
Chinese patent CN 104189952B discloses an injection for correcting skin fold and a preparation method thereof, wherein the injection contains macromolecular polysaccharide, amino acid, water-soluble vitamin, L-carnosine and the like. It is mentioned that the high molecular weight polysaccharide is a water-soluble, non-crosslinked polysaccharide, which is maintained for a short period of time on the skin.
The cross-linked sodium hyaluronate gel is widely used clinically as a tissue filling preparation, and the use concentration is 10-23 mg/mL. Such a product is gel-like, has the dual properties of a solid and a liquid, and is suitable for subcutaneous tissue filling. The main principle is to repair skin pits by increasing the volume of subcutaneous tissues. The metabolism duration of the cross-linked sodium hyaluronate is remarkably prolonged compared with that of non-cross-linked sodium hyaluronate, and the supporting effect of 6-18 months can be maintained. However, these cross-linked sodium hyaluronate are not suitable for filling skin in shallow layers, and have obvious granular feeling, and skin nodules are easily formed, so that the appearance is affected.
Disclosure of Invention
In order to prepare a skin wrinkle-correcting product having a longer degradation time, the present inventors prepared cross-linked sodium hyaluronate in a solution-like formulation for intradermal injection filling. The preparation comprises cross-linked sodium hyaluronate, water-soluble non-cross-linked high molecular polysaccharide or salt form thereof (for example, non-cross-linked sodium hyaluronate), polypeptide, amino acid, vitamin and the like. The product can repair wrinkles by increasing the volume of intradermal tissue, and can also repair the matrix structure of skin cells by nourishing skin.
Accordingly, it is an object of the present invention to provide a cross-linked sodium hyaluronate complex solution formulation. The cross-linked sodium hyaluronate composite solution preparation comprises cross-linked sodium hyaluronate, and water-soluble non-cross-linked high molecular polysaccharide or salt form thereof (such as non-cross-linked sodium hyaluronate), polypeptide, amino acid, vitamin and the like. The cross-linked sodium hyaluronate composite solution preparation can be used for filling and correcting wrinkles such as facial wrinkles, hand wrinkles, eye wrinkles, neck wrinkles, stretch marks and the like. The cross-linked sodium hyaluronate composite solution preparation can be applied to the fields of implanted medical instruments, skin beauty care and the like.
The invention also aims to provide a preparation method of the cross-linked sodium hyaluronate composite solution preparation.
Still another object of the present invention is to provide the use of the above cross-linked sodium hyaluronate composite solution preparation.
According to one aspect, the present invention provides a cross-linked sodium hyaluronate composite solution formulation comprising:
1-20 mg/mL, preferably 4-10 mg/mL, and most preferably 5mg/mL of crosslinked sodium hyaluronate;
0.1-20 mg/mL, preferably 5-15 mg/mL, most preferably 10mg/mL of water-soluble non-crosslinked polymeric polysaccharide or a salt form thereof;
polypeptide 0-20 mg/mL, preferably 0.1-15 mg/mL, more preferably 1-5 mg/mL, and most preferably 2.0 mg/mL;
0-10 mg/mL, preferably 0.1-5.0 mg/mL, more preferably 0.1-1.0 mg/mL, of amino acid;
vitamin is 0-50 μ g/mL, preferably 0.1-30 μ g/mL, 2-10 μ g/mL, and most preferably 5 μ g/mL.
In the invention, the cross-linked sodium hyaluronate can be prepared by chemically cross-linking non-cross-linked sodium hyaluronate.
In the invention, preferably, the pH of the cross-linked sodium hyaluronate composite solution preparation can be 6-8.
In the present invention, preferably, examples of the water-soluble non-crosslinked polymeric polysaccharide or a salt form thereof may include hyaluronic acid, chondroitin sulfate, heparin, etc., and a salt form thereof. More preferably, the water-soluble non-crosslinked polymeric polysaccharide or the salt form thereof is non-crosslinked sodium hyaluronate. The non-crosslinked sodium hyaluronate may be sodium hyaluronate commonly used or commercially available in the art. Preferably, the sodium hyaluronate has a weight average molecular weight of 2 × 105～2×106And D, dalton.
In the present invention, the polypeptide may be an antioxidant polypeptide, such as L-carnosine, glutathione, and the like. Preferably, the polypeptide is L-carnosine.
Amino acids are structural units of proteins. Glycine, alanine and proline are abundant in collagen. In the present invention, the amino acid may be any one or more of the octadecanoic acids required by the human body. In the present invention, the amino acid may be selected from one or more of glycine, leucine, methionine, tyrosine, histidine, threonine, alanine, isoleucine, tryptophan, cystine, lysine, aspartic acid, valine, phenylalanine, proline, serine, glutamic acid, and arginine. Preferably, the amino acid is one or more selected from glycine, alanine and proline. Most preferably, the amino acids consist of glycine, alanine and proline.
In the present invention, the vitamin may be a water-soluble vitamin, including B vitamins, vitamin C, and the like. Preferably, the vitamin is a B vitamin, more preferably vitamin B2.
According to another aspect, the present invention provides a method for preparing the above cross-linked sodium hyaluronate composite solution preparation, comprising the steps of:
step 1) preparation of a cross-linked sodium hyaluronate solution: preparing sodium hyaluronate into a cross-linked sodium hyaluronate aqueous solution;
step 2) preparation of composite solution: preparing water-soluble non-crosslinked polymer polysaccharide or salt form thereof, polypeptide, amino acid and vitamin into water solution;
and 3) mixing the composite solution obtained in the step 2) with the cross-linked sodium hyaluronate solution obtained in the step 1) to obtain the cross-linked sodium hyaluronate composite solution preparation.
Preferably, the method for preparing the cross-linked sodium hyaluronate composite solution preparation of the present invention further comprises the step of sterilizing the cross-linked sodium hyaluronate solution obtained in step 1) and the composite solution obtained in step 2), respectively, before step 3). For example, the crosslinked sodium hyaluronate solution obtained in step 1) is subjected to moist heat sterilization, and the complex solution obtained in step 2) is subjected to filtration sterilization.
In the method for preparing the cross-linked sodium hyaluronate composite solution preparation of the present invention, preferably, the pH of the cross-linked sodium hyaluronate solution may be 6 to 8.
In the method for preparing the cross-linked sodium hyaluronate composite solution preparation of the present invention, preferably, the pH of the composite solution may be 6 to 8.
Preferably, the cross-linked sodium hyaluronate composite solution formulation of the present invention comprises the steps of: preparing 5-30% (g/g) sodium hyaluronate aqueous solution, adding 0.5-20% (g/g) strong base, adding a cross-linking agent (preferably, the mass ratio of the cross-linking agent to the sodium hyaluronate is 0.5-5%), and crosslinking for 2-40 h; after crosslinking, adjusting the pH value to 6.0-8.0, adding a buffer salt solution, diluting the sodium hyaluronate content to 1% -5% (g/g), and then performing moist heat sterilization; preparing water-soluble non-crosslinked high molecular polysaccharide or salt form thereof, polypeptide, amino acid and vitamin into water solution, filtering, sterilizing, and mixing with crosslinked sodium hyaluronate subjected to moist heat sterilization to obtain the crosslinked sodium hyaluronate composite solution preparation. Among them, preferably, the strong base used for preparing the cross-linked sodium hyaluronate solution includes but is not limited to sodium hydroxide, potassium hydroxide; preferably, the buffered salt solution used for dilution includes, but is not limited to, phosphate buffered solutions, acetate buffered solutions, citrate buffered solutions; preferably, the crosslinking agent used to crosslink the sodium hyaluronate includes, but is not limited to, bis-epoxies, divinyl sulfones, for example, 1, 4-butanediol diglycidyl ether may be used.
Preferably, the method for preparing the cross-linked sodium hyaluronate composite solution preparation of the present invention further comprises the step of filling the cross-linked sodium hyaluronate composite solution preparation in a container (e.g., pre-filled syringe, vial or Karl flask) after aseptic filling.
In the method for preparing the cross-linked sodium hyaluronate composite solution formulation of the present invention, preferably, the sodium hyaluronate used for preparing the cross-linked sodium hyaluronate in step 1) may be sodium hyaluronate which is generally used or commercially available in the art. Preferably, the sodium hyaluronate has a weight average molecular weight of 2 × 105～2×106And D, dalton.
In the method for preparing the composite solution preparation of the present invention, the shear viscosity of the crosslinked sodium hyaluronate composite solution preparation is preferably 50 to 1000mPa · s.
According to still another aspect, the present invention provides a use of the above cross-linked sodium hyaluronate composite solution preparation for preparing a product for correcting wrinkles in a human body.
In the above use of the present invention, preferably, the wrinkles of the human body may include, but are not limited to, facial wrinkles, periocular wrinkles, forehead lines, neck lines, hand wrinkles, pregnancy lines, and the like.
Detailed Description
The following specific examples are provided to illustrate the present invention, but the scope of the present invention is not limited by the examples.
The experimental methods in the examples, in which specific conditions are not specified, are generally performed under the conditions described in the manual and the conventional conditions, or under the conditions recommended by the manufacturer; general equipment, materials, reagents and the like used are commercially available unless otherwise specified.
EXAMPLE 1 preparation of Cross-Linked sodium hyaluronate Complex solution formulation-1
10.0g of sodium hyaluronate (weight average molecular weight 120 ten thousand daltons) was taken and added to 90.0g of water for injection. Stirring with a glass rod, and standing at room temperature for 30 min. Adding 5.0g of sodium hydroxide, and uniformly stirring by using a glass rod; then 0.2g of 1, 4-butanediol diglycidyl ether is added to react for 16h at 25 ℃; then 62.5mL of 2M hydrochloric acid was added, and water for injection was added to a total weight of 1000.0 g. Homogenizing for 30min with homogenizer (IKA, T25 digital display, with a dispensing head of 18G). Transferring into 2L Schottky bottle, and performing moist heat sterilization at 121 deg.C for 15min to obtain crosslinked sodium hyaluronate solution for use.
60.0g of sodium hyaluronate (weight average molecular weight of 120 ten thousand daltons), 8.0g of L-carnosine, 0.8g of glycine, 0.8g of alanine, 1.6g of proline and 4mL of vitamin B2 solution (concentration of 5mg/mL) were weighed, dissolved in water for injection, supplemented to 2000.0g, and filtered using a 0.2 μm polyethersulfone filter to obtain a composite solution for use.
Adding 1000.0g of the composite solution into the standby cross-linked sodium hyaluronate solution, oscillating for 10min on a vortex oscillator, standing for 8h at normal temperature, and reversing and uniformly mixing 10 times every 1 h.
The cross-linked sodium hyaluronate composite solution preparation-1 is prepared by the method, and the composite solution is in a solution state. Wherein the content of the cross-linked hyaluronic acid is 5mg/mL, the content of the non-cross-linked sodium hyaluronate is 15mg/mL, the content of the L-carnosine is 2.0mg/mL, the content of the glycine is 0.2mg/mL, the content of the alanine is 0.2mg/mL, the content of the proline is 0.4mg/mL, and the content of the vitamin B2 is 5 mug/mL.
Comparative example 1 preparation of Cross-Linked sodium hyaluronate Complex solution preparation-2
10.0g of sodium hyaluronate (weight average molecular weight 120 ten thousand daltons) was taken and added to 90.0g of water for injection. Stirring with a glass rod, and standing at room temperature for 30 min. Adding 5.0g of sodium hydroxide, and uniformly stirring by using a glass rod; then 0.2g of 1, 4-butanediol diglycidyl ether is added to react for 16h at 25 ℃; then 62.5ml of 2M hydrochloric acid was added and water for injection was added to a total weight of 250.0 g. Homogenizing for 30min with homogenizer (IKA, T25 digital display, with a dispensing head of 18G). Transferring to a 1L Schottky bottle, and performing moist heat sterilization at 121 ℃ for 15min to obtain a cross-linked sodium hyaluronate solution for later use.
4.00g of L-carnosine, 0.4g of glycine, 0.4g of alanine, 0.8g of proline and 2mL of a vitamin B2 solution (concentration: 5mg/mL) were weighed, dissolved in water for injection, used at a constant volume of 1000.0g, and filtered through a 0.2 μm polyethersulfone filter to obtain a composite solution.
Adding 250.0g of the composite solution into 250.0g of the standby cross-linked sodium hyaluronate solution, oscillating on a vortex oscillator for 10min, standing at normal temperature for 8h, and evenly mixing 10 times by reversing every 1 h.
The cross-linked sodium hyaluronate composite solution preparation-2 is prepared by the method, and the composite solution presents a gel shape. Wherein the content of the cross-linked hyaluronic acid is 20mg/mL, the content of the L-carnosine is 2.0mg/mL, the content of the glycine is 0.2mg/mL, the content of the alanine is 0.2mg/mL, the content of the proline is 0.4mg/mL, and the content of the vitamin B2 is 5 mug/mL.
Comparative example 2 preparation of non-crosslinked sodium hyaluronate solution formulation
500mL of a composite solution of 10.0g of sodium hyaluronate (weight average molecular weight: 120 ten thousand daltons), 1.0g of L-carnosine, 0.1g of glycine, 0.1g of alanine, 0.2g of proline and 0.5mL of vitamin B2 (concentration: 5mg/mL) was weighed, and after the sodium hyaluronate was completely dissolved, filtration was performed using a 0.2 μm polyethersulfone filter.
The non-crosslinked sodium hyaluronate composite solution prepared by the above method is in a solution state. Wherein the content of non-crosslinked hyaluronic acid is 20mg/mL, the content of L-carnosine is 2.0mg/mL, the content of glycine is 0.2mg/mL, the content of alanine is 0.2mg/mL, the content of proline is 0.4mg/mL, and the content of vitamin B2 is 5 mug/mL.
Experimental example 1 comparison of shear properties between the crosslinked sodium hyaluronate composite solution formulation-1 prepared in example 1 and the crosslinked sodium hyaluronate composite solution formulation-2 prepared in comparative example 1
The shear viscosity measurement method of the cross-linked sodium hyaluronate composite solution comprises the following steps: at 25 ℃. + -. 0.2 ℃ using a TA rheometer (type DHR-2) at a shear rate of from 0.001s-1～1000s-1Peristaltic scan was performed and recorded at a shear rate of 100s-1The value below is taken as the shear viscosity of the composite solution.
The shear viscosity of the crosslinked sodium hyaluronate composite solution preparation-1 was 219.3mPa.s, and the shear viscosity of the crosslinked sodium hyaluronate composite solution preparation-2 was 2040.7 mPa.s. The higher the specific gravity of the crosslinked sodium hyaluronate, the higher the shear viscosity of the composite solution formulation. The fluidity of the cross-linked hyaluronic acid complex solution preparation-1 is significantly better than that of the cross-linked sodium hyaluronate complex solution preparation-2.
Experimental example 2 comparison of degradation periods of the cross-linked sodium hyaluronate composite solution formulation prepared in example 1 and the non-cross-linked sodium hyaluronate composite solution formulation prepared in comparative example 2
And taking 19mL of each of the crosslinked sodium hyaluronate composite solution preparation-1 and the non-crosslinked sodium hyaluronate composite solution preparation, adding 1U/mL of hyaluronidase solution, reacting at 37 ℃, and taking 2mL of each sample for 30min, 60min, 90min, 120min and 180min respectively to measure the shear viscosity.
Shear viscosity measurement method: at 25 ℃. + -. 0.2 ℃ using a TA rheometer (DHR-2) at a shear rate of from 0.001s-1～1000s-1Peristaltic scan was performed and recorded at a shear rate of 100s-1The value below is taken as the shear viscosity of the composite solution.
The measurement results are shown in Table 1. From the results, the cross-linked sodium hyaluronate composite solution formulation of the present invention significantly prolongs the degradation time.
TABLE 1 shear dynamic viscosity of the enzymatic composite solutions at different time points
Therefore, compared with the common crosslinked sodium hyaluronate filling material, the crosslinked sodium hyaluronate composite solution preparation has lower viscosity and better fluidity; compared with non-crosslinked sodium hyaluronate, the degradation time is longer. The product of the invention can be used for correcting human wrinkles such as facial wrinkles, eye wrinkles, forehead wrinkles, neck wrinkles, hand wrinkles, pregnancy lines and the like by using an intradermal injection mode.
Claims (16)
1. A cross-linked sodium hyaluronate composite solution formulation comprising:
1-20 mg/mL of cross-linked sodium hyaluronate;
0.1-20 mg/mL of water-soluble non-crosslinked polymeric polysaccharide or salt form thereof;
0-20 mg/mL of polypeptide or L-carnosine, excluding 0;
0-10 mg/mL of amino acid, excluding 0;
0-50 mug/mL of vitamin is not included;
wherein the cross-linked sodium hyaluronate composite solution preparation is prepared by a preparation method comprising the following steps:
step 1) preparation of a cross-linked sodium hyaluronate solution: preparing sodium hyaluronate into a cross-linked sodium hyaluronate aqueous solution;
step 2) preparation of composite solution: preparing water-soluble non-crosslinked polymer polysaccharide or salt form thereof, polypeptide or L-carnosine, amino acid and vitamin into aqueous solution;
and 3) mixing the composite solution obtained in the step 2) with the cross-linked sodium hyaluronate solution obtained in the step 1) to obtain the cross-linked sodium hyaluronate composite solution preparation.
2. The crosslinked sodium hyaluronate compound solution preparation according to claim 1, wherein the crosslinked sodium hyaluronate is 4-10 mg/mL, the water soluble non-crosslinked polymeric polysaccharide or salt form thereof is 5-15 mg/mL, the polypeptide or L-carnosine is 0.1-15 mg/mL, the amino acid is 0.1-5.0 mg/mL, and the vitamin is 0.1-30 μ g/mL.
3. The cross-linked sodium hyaluronate composite solution formulation according to claim 1, wherein said polypeptide or L-carnosine is 1-5 mg/mL and said vitamin is 2-10 μ g/mL.
4. The crosslinked sodium hyaluronate composite solution formulation according to claim 1, wherein the crosslinked sodium hyaluronate is 5mg/mL, the water soluble non-crosslinked polymeric polysaccharide or salt form thereof is 10mg/mL, the polypeptide or L-carnosine is 2.0mg/mL, the amino acid is 0.1-1.0 mg/mL, and the vitamin is 5 μ g/mL.
5. The crosslinked sodium hyaluronate composite solution formulation according to claim 1, wherein the pH of the crosslinked sodium hyaluronate composite solution formulation is 6 to 8.
6. The crosslinked sodium hyaluronate composite solution formulation according to claim 1, wherein said water soluble non-crosslinked polymeric polysaccharide or salt form thereof is selected from hyaluronic acid, chondroitin sulfate, heparin, and salt forms thereof.
7. The crosslinked sodium hyaluronate composite solution formulation according to claim 6, wherein the water soluble non-crosslinked polymeric polysaccharide or salt form thereof is non-crosslinked sodium hyaluronate.
8. The crosslinked sodium hyaluronate composite solution formulation according to claim 7, wherein the non-crosslinked sodium hyaluronate has a weight average molecular weight of 2 x 105~2×106And D, dalton.
9. The cross-linked sodium hyaluronate composite solution formulation according to claim 1 wherein the polypeptide is selected from glutathione; and/or
Wherein the amino acid is one or more selected from glycine, leucine, methionine, tyrosine, histidine, threonine, alanine, isoleucine, tryptophan, cystine, lysine, aspartic acid, valine, phenylalanine, proline, serine, glutamic acid and arginine; and/or
The vitamin is a water-soluble vitamin.
10. The cross-linked sodium hyaluronate composite solution formulation according to claim 9 wherein the amino acid is one or more selected from glycine, alanine and proline and the vitamin is selected from B vitamins and vitamin C.
11. The cross-linked sodium hyaluronate composite solution formulation according to claim 9 wherein said amino acid consists of glycine, alanine and proline and said vitamin is vitamin B2.
12. The method for preparing a cross-linked sodium hyaluronate composite solution formulation according to claim 1 comprising the steps of:
step 1) preparation of a cross-linked sodium hyaluronate solution: preparing sodium hyaluronate into a cross-linked sodium hyaluronate aqueous solution;
step 2) preparation of composite solution: preparing water-soluble non-crosslinked polymer polysaccharide or salt form thereof, polypeptide or L-carnosine, amino acid and vitamin into aqueous solution;
and 3) mixing the composite solution obtained in the step 2) with the cross-linked sodium hyaluronate solution obtained in the step 1) to obtain the cross-linked sodium hyaluronate composite solution preparation.
13. The method according to claim 12, further comprising the step of sterilizing the cross-linked sodium hyaluronate solution obtained in step 1) and the complex solution obtained in step 2), respectively, before step 3).
14. The method for preparing the cross-linked sodium hyaluronate composite solution formulation of claim 12 or 13, comprising the steps of: preparing 5-30% g/g sodium hyaluronate aqueous solution, adding 0.5-20% g/g strong base, and adding a cross-linking agent in an amount of 0.5-5% of the mass ratio of sodium hyaluronate, wherein the cross-linking time is 2-40 hours; after crosslinking, adjusting the pH value to 6.0-8.0, adding a buffer salt solution, diluting the sodium hyaluronate content to 1% -5% g/g, and then carrying out damp-heat sterilization; preparing water-soluble non-crosslinked polymer polysaccharide or salt form thereof, polypeptide or L-carnosine, amino acid and vitamin into water solution, filtering, sterilizing, and mixing with crosslinked sodium hyaluronate subjected to moist heat sterilization to obtain the crosslinked sodium hyaluronate composite solution preparation.
15. Use of the cross-linked sodium hyaluronate composite solution formulation according to claim 1 for a product for correcting wrinkles in human body.
16. The use of claim 15, wherein the human wrinkles include facial wrinkles, periocular wrinkles, forehead lines, neck lines, hand wrinkles, stretch marks.
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| CN113230452A (en) * | 2021-05-28 | 2021-08-10 | 易生彬 | Face filler and preparation method thereof |
| CN113813198A (en) * | 2021-09-24 | 2021-12-21 | 西安莲韵医疗美容医院有限公司 | Nutrient solution for improving facial wrinkles and firming skin and preparation method thereof |
| CN114522223A (en) * | 2022-03-24 | 2022-05-24 | 浙江天妍生物科技有限公司 | Injection for correcting skin wrinkles and production process thereof |
| CN114712264B (en) * | 2022-06-08 | 2022-09-09 | 南京天纵易康生物科技股份有限公司 | Synergistic stable sodium hyaluronate composite solution composition and preparation thereof |
| CN115245595B (en) * | 2022-07-28 | 2024-05-24 | 爱博诺德(北京)医疗科技股份有限公司 | Hyaluronic acid-based gel compositions for easy bolus injection |
| CN115944553A (en) * | 2022-12-07 | 2023-04-11 | 华熙生物科技股份有限公司 | Application of oligopeptide in improving stability of cross-linked hyaluronic acid or salt thereof |
| CN115737912B (en) * | 2023-01-09 | 2023-04-28 | 云南云科特色植物提取实验室有限公司 | Preparation method of hyaluronic acid microsphere composite solution preparation with slow release effect |
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